The invention relates to compounds that have multiple beneficial pharmacological effects, and more particularly, to aryl amine-based compounds that inhibit activity of Factor VIIa and/or IMPDH enzyme. The compounds of the present invention and pharmaceutical compositions containing them advantageously may be used as therapeutic agents for treating disorders associated with the activity of Factor VIIa and/or IMPDH.
Inosine monophosphate dehydrogenase (IMPDH) has been shown to be a key enzyme in the regulation of cell proliferation and differentiation. IMPDH is involved in the de novo synthesis of guanosine nucleotides, which are required for cells to divide and replicate. Because B and T lymphocytes depend on the de novo pathway, inhibitors of IMPDH have been shown to possess immunosuppressive activities, as well as antineoplastic, antiviral, and antiparasitic activities. IMPDH inhibitors have been proven advantageous in mammalsxe2x80x94e.g. the prodrug of MPA (CellCept(copyright)) and other IMPDH inhibitors are useful drugs for treating transplant rejection and autoimmune disorders, including HIV. Various other IMPDH inhibitors are in clinical studies, including Vertex compound (VX-497), and/or have been approved for use in humans. See, e.g., Compilation, Current Medicinal Chemistry, Vol. 6, No. 7 (July 1999), Contents: Inhibition of Inosine Monophosphate Dehydrogenase (IMPDH), at 519 (xe2x80x9cOver 300 literature citations now address the characterization, mechanism, and biological functions of IMPDH, its role as a target for both antileukemic and immunosuppressive therapy, and its inhibition by chemotherapeutic agents.xe2x80x9d)
Coagulation factors circulating in the blood, including Factors VII, IX, X, and XI, participate in a series of reactions to produce thrombin and trigger blood coagulation. When the coagulation system is triggered (e.g., when trauma occurs), the coagulation factors are transformed into activated factors (e.g., Factors VIIa, IXa, Xa, XIa, etc.). The activated factors undergo an ordered series of reactions that ultimately lead to the conversion of Factor X to Factor Xa, which then catalyzes the conversion of prothrombin to thrombin. Thrombin is an enzyme that occupies a central position in the coagulation process. Disturbances in the natural balance between pro- and anti-coagulant forces may result in bleeding and/or thrombotic diseases. Consequently, an elevated plasma level of coagulation factors, particularly Factor VIIa, is a risk factor for fatal myocardial infarction and associated with coronary artery disease and other abnormalities of the coagulation system, e.g., thrombosis, ischemic vascular disease, intravascular clotting, stroke, embolisms, and so forth. Inhibitors of Factor VIIa may prove useful in treating these and other diseases.
As may be appreciated, those in the field of pharmaceutical research continue to seek to develop new compounds and compositions having increased effectiveness and bioavailability and/or having fewer side effects. There is particularly an interest in developing agents that can selectively and directly inhibit key enzymes and proteins having significant biolological effects such as IMPDH and Factor VIIa. The compounds of this invention are useful as inhibitors of IMPDH and/or Factor VIIa, and thus may have multiple beneficial pharmacological properties.
The present invention provides compounds of the following formulae (I), their enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts, prodrugs and solvates thereof: 
wherein:
D is a monocyclic or bicyclic ring system optionally containing up to 4 heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of said N, O or S heteroatoms is optionally substituted with oxo (xe2x95x90O), and wherein D is optionally substituted by one to four (CR9R10)nE groups;
A is R3 or R4, provided that if A is R3, then D is a monocyclic or bicyclic heterocyclic ring system wherein a CH2 adjacent to any of N, O or S heteroatoms in said ring is optionally substituted with oxo (xe2x95x90O), and wherein D is optionally substituted by one to four (CR9R10)nE groups;
R3 is a 5- or 6-membered saturated or unsaturated heterocyclic ring system containing up to 4 heteroatoms selected from N, O, and S, said heterocyclic ring system being optionally substituted with 0-3 R5, wherein when R5 is hydroxy, the heterocycle may undergo tautomerization to an oxo species, or exist as an equilibrium mixture of both tautomers;
R4 is selected from H, halogen, NO2, CF3, C0-C4 alkylCN, C1-C4alkoxy-, C0-C4 alkylhydroxy, C1-C4 alkyl-, C1-C4 alkylcarbonyl-, C0-C4 alkylOCOR6, C0-C4 alkylOC(xe2x95x90O)OR6, C0-C4 alkylOC(xe2x95x90O)NR6R7, C0-C4 alkylNR6R7, C0-C4 alkylNR7C(xe2x95x90O)OR6, C0-C4 alkylNR6SO2NR6R7, C0-C4 alkylNR7SO2R6, C0-C4 alkylSR6, C0-C4 alkylS(O)R6, C0-C4 alkylSO2R6, SO3R7, C0-C4 alkylSO2NR6R7, C0-C4alkyl SO2NR7 CO(CR9R10)qR6, C0-C4 alkylCO2R6, C0-C4 alkylCONR6R7, and C0-C4CONR7SO2(CR9R10)qR6;
R5 is selected from H, halogen, NO2, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl, haloalkoxy, OH, oxo, C1-C4alkoxy, C1-C4alkylcarbonyl, CN, NR6R7, SR7, S(O)R7, SO2R7, SO3R7, SO2NR6, CO2R6, and CONR6R7;
R is H or C1-C4alkyl;
R1 and R2 are each independently selected from H, halogen, NO2, C1-C4alkyl, C3-C10cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl, haloalkoxy, OR6, O(CR9R10)rCO2R6, O(CR9R10)mNR6R7, O(CR9R10)pCN, O(CR9R10)rC(xe2x95x90O)NR6R7, C1-C4alkylcarbonyl-, CN, NR6R7, NR7(CR9R10)rCO2R6, NR7OR6, NR7(CR9R10)mOR6, NR7CH[(CR9R10)pOR6]2, NR7C[(CR9R10)pOR6]3, NR7C(xe2x95x90O)R6, NR7(CR9R10)mOR6, NR7(CR9R10)mNR6R7, NR7(CR9R10)mSO2(CR9R10) qR6, SR7, S(O)R7, SO2R7, SO2NR6, SO3R7, CO2R6, and CONR6R7; or, alternatively, R1 and R2, when on adjacent carbon atoms, may be taken together to be methylenedioxy or ethylenedioxy;
R6, R7 and R8 are each independently selected from H, C1-C6alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6 alkylcarbonyl, C3-C7 cycloalkyl(C0-C5 alkyl)carbonyl, C1-C6 alkoxycarbonyl, aryl(C0-C5alkyl)carbonyl, aryl(C1-C5 alkoxy)carbonyl, heterocyclic(C0-C5 alkyl)carbonyl, heterocyclic(C1-C5 alkoxy)carbonyl, C1-C6alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C0-C4alkylaryl, C0-C4alkylheterocyclic, wherein said cycloalkyl, aryl or heterocyclic groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4alkyl, hydroxy, C1-C4 alkoxy, F, Cl, Br, haloalkyl, NO2 and CN;
or, alternatively, R6 and R7, or R6 and R8, or R7 and R8, when both substituents are on the same nitrogen atom [as in (xe2x80x94NR6R7) or (xe2x80x94NR7R8)], can be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from 1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, 3-azabicyclo[3,2,2]nonan-3-yl, and 1-tetrazolyl, said heterocycle being optionally substituted with 0-3 groups selected from oxo, C0-C4alkylOH, C0-C4alkylOC1-C4alkyl, C0-C4alkylCONH2, C0-C4alkylCO2C0-C4alkyl, C1-C6alkyl, C1-C4 alkoxy, C3-C7 cycloalkyl, xe2x80x94C0-C6 alkylcarbonyl, C3-C7 cycloalkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C7 cycloalkoxycarbonyl, xe2x80x94NHCOalkyl, aryl, heteroaryl, arylalkoxycarbonyl, heteroarylalkoxycarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl;
B is a monocyclic or bicyclic ring system optionally containing up to 4 heteroatoms selected from N, O, and S, and wherein a CH2 adjacent to any of said N, O or S heteroatoms is optionally substituted with oxo (xe2x95x90O), and wherein B is optionally substituted by one to four R11 groups;
R9 is H or C1-C4alkyl;
R10 is selected from H or C1-C4 alkyl, C1-C4 alkylhydroxy, C1-C4alkylaryl or C1-C4alkylheteroaryl, wherein said aryl or heteroaryl group may be substituted with 0 -3 groups independently selected from H, halogen, NO2, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl, haloalkoxy, OH, C1-C4alkoxy, C1-C4alkylcarbonyl, CN, NR6R7, SR6, S(O)R6, SO2R6, SO3R6, SO2NR6, CO2R6, and CONR6R7;
R11 is selected from H, halogen, NO2, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl, haloalkoxy, C1-C4alkoxy-, OR6, O(CR9R10)rCO2R6, O(CR9R10)mNR6R7, O(CR9R10)pCN, O(CR9R10)rC(xe2x95x90O)NR6R7, C1-C4alkylcarbonyl-, CN, NR6R7, NR7(CR9R10)rCO2R6, NR7OR6, NR7(CR9R10)mOR6, NR7CH[(CR9R10)pOR6]2, NR7C[(CR9R10)pOR6]3, NR7C(xe2x95x90O)R6, NR7(CR9R10)mOR6, NR7(CR9R10)mNR6R7, NR7(CR9R10)mSO2(CR9R10)qR6, SR7, S(O)R7,SO2R7, SO2NR6, SO3R7, CO2R6, and CONR6R7;
E is selected from H, halogen, NO2, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloalkyl, haloalkoxy, OR6, CN, CHO, CO2R6, CONR6R7, OCOR6, OC(xe2x95x90O)OR6, OC(xe2x95x90O)NR6R7, OCH2CO2R6, C(xe2x95x90O)R6, NR6R7, NR7C(xe2x95x90O)R6, NR7C(xe2x95x90O)OR6, NR7C(xe2x95x90O)C(xe2x95x90O)OR6, NR7C(xe2x95x90O)C(xe2x95x90O)NR6R7, NR7C(xe2x95x90O)C(xe2x95x90O)(C1-C6alkyl), NR7C(xe2x95x90NCN)OR6, NR7C(xe2x95x90O)NR6R7, NR7C(xe2x95x90NCN)NR6R7, NR7C(xe2x95x90NR6)NR7R8, NR6SO2NR6R7, NR7SO2R6, SR6, S(xe2x95x90O)R6, SO2R6, SO3R7, SO2NR6R7, NHOR6, NR6NR7NR8, N(COR6)OH, N(CO2R6)OH, CO2R6, CONR7(CR9R10)rR6, CO(CR9R10)pO(CHR9)qCO2R6, CO(CR9CR10)rOR6, CO(CR9R10)pO(CR9R10)qR6, CO(CR9CR10)rNR6R7, OC(O)O(CR9R10)mNR6R7, O(CO)N(CR9R10)rR6, O(CR9R10)mNR6R7, NR7C(O)(CR9R10)rR6, NR7C(O)(CR9R10)rOR6, NR7C(xe2x95x90NC)(CR9R10)rR6, NR7CO(CR9R10)rNR6, R7, NR7(CR9R10)mOR6, NR7(CR9R10)rCO2R6, NR7(CR9R10)mNR6R7, NR7(CR9R10)nSO2(CR9R10)qR6, CONR7(CR9R10)nSO2(CR9R10)qR6, SO2NR7(CR9R10)n CO(CR9R10)qR6, SO2NR6(CR9R10)mOR6, C3-C10 cycloalkylmethyl, aryl, heterocyclic and alkylaryl, wherein said aryl groups may be substituted with 0-2 substituents independently selected from R12;
R12 at each occurrence is independently selected from H, halogen, NO2, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl, haloalkoxy, oxo, OR6, O(CR9R10)rCO2R6, O(CR9R10)mNR6R7, O(CR9R10)pCN, O(CR9R10)rC(xe2x95x90O)NR6R7, C1-C4alkylcarbonyl-, CN, NR6R7, NR7(CR9R10)rCO2R6, NR7OR6, NR7(CR9R10)mOR6, NR7CH[(CR9R10)pOR6]2, NR7C[(CR9R10)pOR6]3, NR7C(xe2x95x90O)R6, NR7(CR9R10)mOR6, NR7(CR9R10)mNR6R7, NR7(CR9R10)mSO2(CR9R10)qR6, SR7, S(O)R7, SO2R7, SO2NR6, SO3R7, CO2R6, and CONR6R7;
n is an integer having a value from 0-4;
m is an integer having a value from 2-6;
p is an integer having a value from 1-3;
q is an integer having a value from 0-3; and
r is an integer having a value from 0-6.
The present invention also provides pharmaceutical compositions comprising the compounds of formula (I) and methods of treating IMPDH-associated and/or Factor VIIa-associated disorders using the compounds of formula I.
Listed below are definitions of various terms used in the specification and claims to describe the present invention.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain alkyl.
The term xe2x80x9cCintegerxe2x80x94Cintegerxe2x80x9d refers to a variable number of carbon atoms in a group depending on the integer values, as in C0-C4alkyl, which is meant to indicate a straight or branched alkyl group containing 0-4 carbon atoms. A group with 0 (zero) carbon atoms indicates that the carbon atom is absent, i.e. there is a direct bond connecting adjacent groups. For example, the term xe2x80x9cC0-C4 alkylhydroxyxe2x80x9d includes hydroxy as well as alkyl groups having one to four carbon atoms substituted by hydroxy.
Similarly, D is defined as a ring which may be substituted with the group xe2x80x9c(CR9R10)nExe2x80x9d and the subscript n may be 0. This is meant to indicate that the group E may be directly connected to D by a bond, i.e. D-E.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine or iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbons having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, and biphenyl groups which may be optionally substituted.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain alkenyl groups.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain alkynyl.
The term xe2x80x9ccycloalkylxe2x80x9d refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
The term xe2x80x9csaturatedxe2x80x9d means partially or fully saturated, unless otherwise indicated.
The term xe2x80x9ccarbocyclicxe2x80x9d refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, which is a 3 to 7 membered monocyclic, or a 7 to 11 membered bicyclic group, and all the atoms in the ring are carbon atoms. Exemplary groups include phenyl, naphthyl, anthracenyl, cyclohexyl, cyclohexenyl, and the like.
The terms xe2x80x9cheterocyclexe2x80x9d and xe2x80x9cheterocyclicxe2x80x9d refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, which is a 3 to 7 membered monocyclic, or a 7 to 11 membered bicyclic group, which has at least one heteroatom in at least one carbon-containing ring. Each heterocyclic ring may contain 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached via a nitrogen or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
As used herein the term xe2x80x9ctreatingxe2x80x9d includes prophylactic and therapeutic uses, and refers to the alleviation of symptoms of a particular disorder in a patient, the improvement in symptoms or conditions associated with a particular disorder, or the prevention of a particular physiological response, such as an immune response (as with transplant rejection). The term xe2x80x9cpatientxe2x80x9d refers to a mammal, preferably a human.
The compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomers of the compounds disclosed herein are expressly included within the scope of the present invention. Each stereogenic carbon may be of the R or S configuration.
One skilled in the field can select substituents and variables thereof that result in stable compounds, which are contemplated within the present invention. The term xe2x80x9cstablexe2x80x9d as used herein refers to compounds which possess sufficient stability to allow for their manufacture and which maintain their integrity for a sufficient period of time to be useful as therapeutic or diagnostic agents.
As used herein, the compounds of this invention are defined to include pharmaceutically acceptable derivatives and prodrugs thereof. A xe2x80x9cpharmaceutically acceptable derivative or prodrugxe2x80x9d includes any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of the invention. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of the present invention when such compound is administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system). Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to a compound of the present invention.
Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases known to those skilled in the art. Examples of suitable acid salts include, but are not limited to, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, filmarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, trifluoroacetic, tosylate and undecanoate. Other acids, for example oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and are contemplated as within the scope of the invention.
Salts derived from appropriate bases include, but are not limited to, the following: alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C1-4 alkyl)4+ salts. The present invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternization.
Preferred compounds according to the invention are those having the formulae (Ia) or (Ib), 
and/or pharmaceutically-acceptable salts, hydrates or prodrugs thereof, wherein:
A is R3 or R4;
B is a monocyclic or bicyclic ring system substituted with one to two R11 groups;
D is a monocyclic or bicyclic heterocyclic or carbocyclic ring system;
D1 is a monocyclic or bicyclic heterocyclic ring system;
R3 is selected from a 5 or 6 membered saturated or fully or partially unsaturated heterocyclic ring, including without limitation oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, diazolyl, and pyrazolyl, said R3 group being optionally substituted with one to two groups selected from hydrogen, halogen, NO2, C1-C4alkyl, haloalkyl, haloalkoxy, OH, oxo, C1-C4alkoxy, C1-C4alkylcarbonyl, CN, NH2, NH(C1-4alkyl), and N(alkyl)2;
R4 is selected from H, halogen, NO2, CF3, C0-C4 alkylCN, C1-C4alkoxy-, C0-C4 alkylhydroxy, C1-C4 alkyl-, C1-C4 alkylcarbonyl-, C0-C4alkylOCOR6, C0-C4 alkylNR6R7, C0-C4 alkylNR7C(xe2x95x90O)OR6, C0-C4 alkylCO2R6, and C0-C4 alkylCONR6R7;
R is H or C1-C4alkyl;
R9 and R10 are selected from H and C1-C4 alkyl;
R1 is hydrogen, halogen, NO2, C1-C4alkyl, C3-C7cycloalkyl, C2-C6alkenyl, haloalkyl, haloalkoxy, OR6, CN, NR6R7, NR7C(xe2x95x90O)R6, CO2R6, or CONR6R7;
E is selected from hydrogen, halogen, NO2, C1-C4alkyl, C3-C7cycloalkyl, C2-C6 alkenyl, haloalkyl, haloalkoxy, OR6, CN, CO2R6, CONR6R7, OCH2CO2R6, C(xe2x95x90O)R6, NR6R7, NR7C(xe2x95x90O)R6, NR7C(xe2x95x90O)NR6R7, NR6SO2NR6R7, NR7SO2R6, NHOR6, NR7C(O)(CR9R10)r,R6, NR7C(O)(CR9R10)rOR6, NR7CO(CR9R10)rNR6R7, NR7(CR9R10)mOR6, NR7(CR9R10)rCO2R6, NR7(CR9R10)mNR6R7, C3-C7cycloalkylmethyl, aryl, heterocyclic and C1-C4alkylaryl;
R6 and R7 are each independently selected from H, C1-C4alkyl, C3-C7cycloalkyl, C2-C6alkenyl, C1-C4alkylcarbonyl, C3-C7cycloalkyl(C0-C5 alkyl)carbonyl, C1-C4alkoxycarbonyl, aryl(C0-C4alkyl)carbonyl, aryl(C1-C4 alkoxy)carbonyl, heterocyclic(C0-C4alkyl)carbonyl, heterocyclic(C1-C4 alkoxy)carbonyl, C0-C4alkylaryl, C0-C4alkylheterocyclic, wherein said cycloalkyl, aryl or heterocyclic groups are substituted with 0-2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4 alkoxy, F, Cl, Br, haloalkyl, NO2 and CN;
or, alternatively, R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocycle selected from 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, and 1-tetrazolyl, said heterocycle being optionally substituted with 0-2 groups selected from oxo, C0-C4alkylOH, C0-C4alkylOC1-C4alkyl, C0-C4alkylCONH2, C0-C4alkylCO2C1-C4alkyl, C1-C6alkyl, C1-C4 alkoxy, C3-C7cycloalkyl, xe2x80x94C0-C4alkylcarbonyl, C1-C6 alkoxycarbonyl, xe2x80x94NHCOalkyl, aryl, and heteroaryl;
R11 is selected from H, halogen, NO2, C1-C4alkyl, C3-C10 cycloalkyl, C2-C6alkenyl, C2-C6alkynyl, haloalkyl, haloalkoxy, OR6, O(CR9R10)rCO2R6, O(CR9R10)mNR6R7, O(CR9R10)pCN, O(CR9R10)rC(xe2x95x90O)NR6R7, C1-C4alkylcarbonyl-, CN, NR6R7, NR7(CR9R10)rCO2R6, NR7OR6, NR7(CR9R10)mOR6, NR7CH[(CR9R10)pOR6]2, NR7C[(CR9R10)pOR6]3, NR7C(xe2x95x90O)R6, NR7(CR9R10)mOR6, NR7(CR9R10)mNR6R7, NR7(CR9R10)mSO2(CR9R10)qR6, SR7, S(O)R7, SO2R7, SO2NR6, SO3R7, CO2R6, and CONR6R7;
m is an integer having a value from 2-4;
n is an integer having a value from 0-4;
r is an integer having a value from 0-4; and
s is an integer having a value of 0 to 2.
In compounds of formula (I), preferred ring systems for xe2x80x9cBxe2x80x9d are selected from: 
More preferred are compounds according to formula (Ic), or pharmaceutically-acceptable salts, hydrates or prodrugs thereof, 
in which each of A, R1, R, B, E, R9 and R10 are defined as above;
J1, J2, J3, J4, and J5 are selected from carbon and nitrogen, provided that no more than four of J1, J2, J3, J4, and J5 are nitrogen;
the group or groups (CR9R10)nE are attached to any one or more of J1, J2, J3, J4, and J5 that are carbon atoms; and s is 1 or 2.
Even more preferred are compounds according to formula (Id), or pharmaceutically-acceptable salts, hydrates or prodrugs thereof, 
in which
A, R1, R, B, J1, J2, J3, J4, and J5 are defined as immediately above for compounds of formula (Ic);
R7a selected from H, C1-C4alkyl, and C3-C7cycloalkyl;
R9 and R10 are selected from H and C1-C4alkyl;
n and r are selected from 0, 1, 2, 3, or 4; and
R6 and R7 are each independently selected from H, C1-C4alkyl, C3-C7cycloalkyl, C2-C6alkenyl, C1-C4alkylcarbonyl, C3-C7cycloalkyl(C0-C5 alkyl)carbonyl, C1-C4alkoxycarbonyl, aryl(C0-C4alkyl)carbonyl, aryl(C1-C4 alkoxy)carbonyl, heterocyclic(C0-C4alkyl)carbonyl, heterocyclic(C1-C4 alkoxy)carbonyl, C0-C4alkylaryl, C0-C4alkylheterocyclic, wherein said cycloalkyl, aryl or heterocyclic groups are substituted with 0-2 substituents independently selected from C1-C4alkyl, hydroxy, C1-C4 alkoxy, F, Cl, Br, haloalkyl, NO2 and CN;
or, alternatively, R6 and R7 taken together with the nitrogen atom to which they are attached form a heterocycle selected from 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, 1-piperazinyl, 1-imidazolyl, and 1-tetrazolyl, said heterocycle being optionally substituted with 0-2 groups selected from oxo, C0-C4alkylOH, C0-C4alkylOC1-C4alkyl, C0-C4alkylCONH2, C0-C4alkylCO2C1-C4alkyl, C1-C6alkyl, C1-C4 alkoxy, C3-C7cycloalkyl, xe2x80x94C0-C4alkylcarbonyl, C1-C6 alkoxycarbonyl, xe2x80x94NHCOalkyl, aryl, and heteroaryl.
The compounds of the present invention may be synthesized using conventional techniques known in the art. Advantageously, these compounds are conveniently synthesized from readily available starting materials. Additionally, illustrative general synthetic schemes for making compounds of the present invention are set forth below. The various steps in the synthesis may be performed in an alternate order to give the desired compound(s). The groups A, D, R1, R6, R7, in the synthetic schemes below are intended to designate the groups as recited in the claims. The group X in the schemes refers to halogen, unless otherwise indicated.
The preparation of heterocycles useful to this invention is described in the literature, e.g., Katritzky et al, xe2x80x9cComprehensive Heterocyclic Chemistry, The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds,xe2x80x9d (Pergamon Press New York, 1984 [1st ed.], and 1996). 
Reaction of an appropriately-substituted amine (1) with a reagent such as 1,1xe2x80x2-thiocarbonyldi-2(1H)-pyridone,1,1xe2x80x2-thiocarbonyldiimidazole or thiophosgene in a solvent such as methylene chloride or dioxane yields the isothiocyanate (2). Treatment of the isothiocyanate (2) with sodium salt of cyanamide yields the sodium salt of N-cyanothiourea (3), which is cyclized to the substituted 1,2,4-aminotriazole (II), using an appropriately-substituted hydrazine and a dehydrating agent such as EDC or DCC. 
An appropriately-substituted amine (1) can be reacted with diphenyl cyanocarbonimidate to yield the N-cyano-O-phenylisourea (4). Cyclization of compound (4) to the substituted triazole (II) is achieved using an appropriately-substituted hydrazine and a solvent such as acetonitrile. 
Acylisothiocyanates (5) are useful intermediates in the production of some compounds of this invention. Compounds (5) are commercially available or can be readily prepared by reaction of an acid chloride with sodium or potassium isothiocyanate in an inert solvent such as dioxane. Acid chlorides are either commercially available or can be readily prepared by reaction of a carboxylic acid and a reagent such as thionyl chloride, or oxalyl chloride in the presence of a catalytic amount of DMF, in an inert solvent such as chloroform or methylene chloride. Reaction of an appropriately-substituted amine (1) with an acylisothiocyanate (5) yields the thiourea (6). The thiourea (6) is cyclized to (III) using hydrazine in a solvent such as EtOH or a solvent mixture such as THF and EtOH, at a temperature preferably between 60xc2x0 C. and the boiling point of the solvent(s) utilized. 
Reaction of an appropriately-substituted amine (1) with an activating agent such as 1,1xe2x80x2 carbonyldiimidazole followed by treatment with an appropriately-substituted hydrazine yields the carbonylhydrazide (7). The carbonylhydrazide (7) on treatment with 1,2-dibromotetrachloroethane and triphenylphosphine in the presence of a suitable base such as TEA and an appropriate solvent such as acetonitrile yields compound (IV). 
Reaction of thiourea (6) (see Scheme 3), with a base such as sodium hydroxide or sodium hydride followed by an alkylating agent such as methyl iodide gives the S-methylisothiocarbamoyl intermediate (8). Treatment of (8) with hydroxylamine in the presence of a suitable solvent such as EtOH or bu-OH at a temperature preferably between 60xc2x0 C. and 110xc2x0 C. results in cyclization to the desired 3-amino-1,2,4-oxadiazole (V). 
Reaction of acyl isothiocyene with D-CONHNH2 in EtOH yields thiourea (9). Thiourea can be cyclized to the desired heterocycle (VI) using a dehydrating agent such as methanesulphonic acid, in an inert solvent such as toluene or xylene, at a temperature preferably between 80xc2x0 C. to 140xc2x0 C. 
Reaction of an appropriately-substituted isothiocyanate (2) (see Scheme 1) and an amidoxime in a solvent, such as chloroform or toluene, at a temperature preferably between 60xc2x0 C. and 110xc2x0 C. results in the production of the desired heterocycle (VII). Amidoximes useful to this invention are either commercially available or can be readily prepared by methods known to one skilled in the art. One such method involves reaction of a nitrile with anhydrous hydrochloric acid in anhydrous MeOH followed by reaction of the resulting imidate with hydroxylamine. 
The coupling of amines with haloaryl compounds has been described in the literature, e.g., in xe2x80x9cRational Development of Practical Catalysts for Aromatic Carbon-Nitrogen Bond Formation,xe2x80x9d Accounts of Chemical Research, Vol. 31 (1998), at pp. 805-818. Reaction of an appropriately-substituted aniline (1) with an appropriately-substituted haloaryl compound (10) in the presence of a catalyst such as tris(dibenzylideneacetone)dipalladium, a ligand such as BINAP, a base such as sodium tert-butoxide, and a solvent such as toluene or dioxane, preferably at a temperature between 80-110xc2x0 C., results in production of the desired diarylamines (VIII).
Bromo- or iodo-aryl intermediates such as 3-bromobiphenyl are commercially available or may be readily prepared by methods known to one skilled in the art. One such method involves bromination of the aryl ring with Br2 in the presence of iron. See also Carey et al., xe2x80x9cAdvanced Organic Chemistry,xe2x80x9d at Chap. 11 (3rd edition, Plenum Press New York, 1990). 
Reaction of an appropriately-substituted isocyanate (2) with a ketone in the presence of a base such as sodium hydride and an alkylating agent such as methyl iodide gives a thiomethyl intermediate (11). Treatment of the intermediate (11) with hydroxylamine in a solvent such as ethyl or butyl alcohol at a temperature preferably between 60-120xc2x0 C. yields the appropriately-substituted 3-aminoisoxazoles (IX). Ketones useful to this invention are either commercially available or can be readily prepared by several methods, such as Friedel-Crafts acylation (see Carey, supra); or by hydrolysis of an enol ether or oxidation of an alcohol (see Larock et al., xe2x80x9cComprehensive Organic Transformations, A Guide to Functional Group Preparationsxe2x80x9d [VCH Publishers, New York, 1989]). 
Reaction of an amine (1) with an amino acid in the presence of an activating agent such as 1,1xe2x80x2-carbonyldiimidazole in a suitable solvent such as THF yields amide (12). Amides also may be readily prepared by a number of methods including reaction of an amine with an acid chloride, or coupling of a carboxylic acid and the amine in the presence of a variety of coupling agents such as EDC or DCI, in the presence of an amine base. The coupling reaction may be enhanced by the addition of 1-hydroxybenzotriazole or similar additives. Reaction of the amide (12) with Lawesson""s reagent in the presence of a base such as pyridine at a temperature preferably between 80-120xc2x0 C. yields the appropriately-substituted 5-aminothiazoles (X). 
Reaction of an isothiocyanate (2) with ammonia in a solvent such as dioxane yields thiourea (12). Treatment of the thiourea (13) with an acylbromide, in the presence of a solvent such as EtOH or dioxane, at a temperature preferably between 60xc2x0 C. and 110xc2x0 C., yields the desired 2-amino-1,3-thiazoles (XI). Acyl bromides are either commercially available or readily prepared by methods known in the field. 
An appropriately-substituted isothiocyanate (2) is reacted with an aminoalcohol in a suitable solvent such as dioxane to yield the thiourea. Treatment of the thiourea with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate in the presence of a base such as TEA in a solvent such as acetonitrile yields desired 2-amino-1,3-oxazolines (XII). Aminoalcohols (14) are either commercially available or can be readily prepared by several methods. One method is reduction of azidoketones of the type described in schemes 15a-15d, either by catalytic hydrogenation in the presence of Pd/C in a solvent such as EtOH or EtOAc, or by a hydride reagent such as lithium aluminum hydride in a solvent such as dioxane or THF. 
Reaction of an isothiocyanate (2) with a xcex2-ketoamine in the presence of a base such as TEA and a solvent such as dioxane yields the thiourea (15). Reaction of the thiourea in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or EDC, in a solvent such as dioxane or toluene, at a temperature preferably between 60xc2x0 C. and 110xc2x0 C., yields the desired 2-aminooxazoles (XIII). xcex2-ketoamines are either commercially available or can be readily prepared by several methods. One method is reduction of azidoketones of the type described in schemes 15a-15d, by phosphine reagents such as triphenylphosphine in a solvent such as dioxane, followed by the addition of water or dilute ammonium hydroxide. 
Reaction of an appropriately-substituted isothiocyanate (2) with an acylazide of the type described in schemes 15a-15d in the presence of a phosphine such as triphenyphosphine in a solvent such as DCM or dioxane at a temperature from rt to 100xc2x0 C., also yields compounds (XIII). One skilled in the field will recognize that caution should be exercised while handling organic azides. 
Treatment of the xcex1-bromoketone (16) with sodium azide in a solvent such as acetone, generally at rt, yields the desired xcex1-azidoketones (XIV) useful as intermediates in this invention. xcex1-Bromoketones (16) are commercially available. Alternatively, xcex1-bromoketones can be readily prepared from a ketone [CH3xe2x80x94C(xe2x95x90O)D], by (a) reaction with a brominating agent such as bromine in acetic acid or pyridinium bromide perbromide and 30% hydrobromic acid; (b) reaction with a carboxylic acid, iso-butylchloroformate and N-methylmorpholine to provide the mixed anhydride, which on treatment with diazomethane (CH2N2) gives the xcex1-diazoketone. Reaction of the xcex1-diazoketone with either HBr gas in a solvent such as ether or dioxane, or aqueous 48% HBr, provides the xcex1-bromoketone (16); or (c) reaction with sulfuric acid and bromine which yields the xcex1,xcex1-dibromoketone, which on treatment with diethylphosphite and TEA yields the xcex1-(mono)bromoketone (16). 
Reaction of an aryl bromide (17) with tributyl(1-ethoxyvinyl) tin and bis-(triphenylphosphine)palladium dichloride provides an intermediate enol ether. Treatment of the enol ether with N-bromosuccinamide at a temperature from 0xc2x0 C. to rt yields the xcex1-bromoketone (18). As described in 15a, treatment of the xcex1-bromoketone with sodium azide in acetone gives the xcex1-azidoketone (XV). 
Reacting a commercially available cyanuric halide (19) such as cyanuric chloride with an aryl Grignard reagent yields the 2-aryl substituted-4,6-dichlorotriazine (20). Treatment of the dichlorotriazine (20) with an aniline (1) in a solvent such as acetone or dioxane with or without the addition of a base such as potassium carbonate, yields the intermediate 2-arylamino-6-aryl-4-chloro triazine (21). The remaining chloro group on the triazine may be replaced with an amine (NR6R7), in a solvent such as dioxane at a temperature preferably between 60-140xc2x0 C.; with a sodium salt of a thiol (NaSR7) in an inert solvent; or with a sodium alkoxide (NaOR6) in an appropriate alcoholic or inert solvent such as dioxane or toluene to provide triazines of type (XVI). 
Consecutive displacement of the chloro groups in cyanuric chloride by nucleophiles can be accomplished by careful choice of reaction conditions with particular attention to the reaction temperature and order of nucleophile addition. (See, e.g., monosubstitution of cyanuric cloride in Cambell et a.., J. Org. Chem., 26, 2786 (1961); disubstitution of a triazine in Thurston et al., J. Amer. Chem. Soc. 73, 2981 (1954); and trisubstitution shown in Controulis et al, J. Amer. Chem. Soc. 67, 1946, (1945)). In the above Scheme 17, reaction of cyanuric chloride (19) with an aniline (1) at a temperature preferably between xe2x88x9245xc2x0 C. and rt yields the 2-arylamino-4,6-dichlorotriazine (22). Addition of a second amine to the 2-arylamino-4,6-dichlorotriazine (22) at an extended period of time at rt (or preferably less than 40xc2x0 C.), provides the monochlortriazine intermediate (23). Treatment of the intermediate (23) with an amine at a temperature preferably between 60xc2x0 C. and 140xc2x0 C. provides the trisubstituted triazine (XVII). 
Monochlorotriazine intermediate (23) (see Scheme 17), is coupled with an aryl(trialkyl)tin or arylboronic acid or heteroaryl(trialkyl)tin or heteroarylboronic acid, in the presence of a palladium catalyst such as Pd(PPh3)4 to provide aryl or heteroaryl substituted triazines of type (XVIII). 
Reaction of an appropriately-substituted aniline (1) with 1,3 bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea and TEA yields the bis-tert-butoxycarbonylguanidine (24). Cleavage of Boc groups using an acid such as TFA or 4N HCl in dioxane yields the guanidine salt (25). There are many methods of liberating the free base of a guanidine including treatment with a base, such as sodium methoxide in anhydrous MeOH, followed by filtration to remove the salt, or stirring with a commercially available strongly basic resin, followed by filtration, and evaporation of the solvent. The guanidine was treated with a xcex2-ketoester and heated in a suitable solvent such as EtOH or dioxane at a temperature preferably between 50xc2x0C.-150xc2x0 C. to yield the pyrimidinone (XI). More than one isomeric pyrimidone may be produced during this reaction, and the desired product may require purification by chromatography or recrystalization. Pyrimidones are also useful intermediates and can be readily converted to the chloropyrimidine by treatment with phosphoryl chloride. Displacement of the chloro group of pyrimidines can be accomplished with a variety of nucleophiles in a manner similar to that described in Scheme 16.
Reaction of guanidine (25) (see Scheme 19) with an xcex1-bromoketone in the presence of a base such as potassium carbonate in a solvent such as DMF provides the desired 2-aminoimidazoles of type (X). More than one isomeric imidazole can form during this reaction, and the desired product can be obtained by a suitable chromatographic method or by recrystalization. 
Aryl boronic acids and esters of type (26), where X is not Br or I, may be prepared from the corresponding arylbromide (26a) by treatment with a palladium catalyst such as [1,1xe2x80x2-Bis(diphenylphosphino)-ferrocene] dichloropalladium (II) and bis(pinacolato)diboron, as reported by Ishayama et al., J. Org. Chem., (1995) 7508 -7510. Aryl boronic esters may be converted to the corresponding boronic acids by several methods including treatment with aqueous HCl. In a variation of the synthesis, the nitrogen may be masked as a nitro group and later reduced by several means including metal reductions, such as by treatment with tin chloride in HCl or by refluxing the nitro compound with zinc in the presence of CaCl2 in a solvent such as EtOH, or in certain cases the nitro group may be reduced by catalytic hydrogenation in the presence of catalysts such as Pd/C. The conditions for the reduction of nitro groups are detailed in several references including Hudlicky, M., xe2x80x9cReductions in Organic Chemistryxe2x80x9d, 2nd Ed., ACS Monograph 188 (1996), pp. 91-101. In a second variation of the synthesis, the aryl bromide is allowed to remain through the entire synthesis and elaborated to the boronic acid at the end. This may eliminate the need for a protecting group. 
Suzuki-type cross coupling of an aryl boronic acid or ester (26) with an appropriate bromoheterocycle (27) in the presence of a suitable catalyst such as Pd(PPh3)4 yields the desired protected amide (28) (see, e.g., Miyaura et al., Synth. Comm., 11(7) (1981), at pp. 513-19; Suzuki et. al., J. Am. Chem. Soc. 111:513 (1989); and Kalinin, Russ. Chem. Rev. 60:173 (1991)). The amide (28) may be deprotected as known to one skilled in the art (see, e.g., Greene and Wuts, Protective Groups in Organic Synthesis,xe2x80x9d (John Wiley and Sons, Inc., New York, N.Y. 1991). For example, if the protecting group is acetyl, the product may be deprotected by treatment with aqueous KOH at a concentration of 0.5 N to 5 N at rt to 100xc2x0 C. for a period between 0.5 h and 24 h, to provide amine (29), an intermediate for making compounds according to the invention. Compounds (26) can be prepared as shown in scheme 21. 
Aryl boronic acid (30) may be reacted with 5-bromothiazole in the presence of Pd(PPh3)4, to provide (31). Alternatively, aryl boronic acid (30) may be reacted with oxazolone in the presence of copper (II) acetate and an amine base such as pyridine to provide intermediate (32). Compounds (31) and (32) may be deprotected by an appropriate method. Copper has been shown to be an effective catalyst for cross coupling of aryl boronic acids to N-unsubstituted heterocycles as described by Chan. et al., Tetrahed. Lett. 39:2933-2936 (1998); and Lam et al., Tetrahed. Lett. 39:2941-2944 (1998). This results in compounds in which the heterocycle is attached to the aryl ring through nitrogen rather than carbon. 
Oxazoles may be prepared by 1,3 dipolar cycloaddition of the corresponding aldehyde (33) and (p-tolylsulfonyl)methyl isocyanate (TOSMIC) (34). The aldehyde may be commercially available or prepared from the corresponding methyl group by oxidation with reagents such as CrO3, MnO2, and ammonium cerium (IV) nitrate. These methods are well known to one skilled in the art and described in Hudlicky, M., xe2x80x9cOxidations in Organic Chemistryxe2x80x9d, ACS Monograph 186 (1990). The nitro group in intermediate (34) is reduced to an amine (35) as discussed above in Scheme 23. Synthesis of 5-membered heterocycles by 1,3-dipolar cycloaddition is also described by Padwa, xe2x80x9c1,3-Dipolar Cycloaddition Chemistry,xe2x80x9d Vols. 1 and 2 (John Wiley and Sons, New York, N.Y., 1984). 
Halonitrobenzenes (36) are either commercially available or can be readily prepared by methods known to one skilled in the art. Displacement of halonitrobenzenes (36) with a variety of nucleophiles produces compounds of structure (37). In one example, heating (36a) with a nucleophilic heterocycle such as triazole with or without the addition of a base provides the intermediate nitro compound which may be reduced as previously described to provide amines (37a). Alternatively, simple organic nucleophiles such as cyanide can be reacted with halonitrobenzene (36b) to provide an intermediate nitrocompound which can be reduced by many methods to produce amine (37b).
The compounds of the present invention inhibit IMPDH enzyme and are thus useful in the treatment of disorders which are mediated by IMPDH. Additionally, inventive compounds are inhibitors of the activated coagulation serine protease known as Factor VIIa, and may inhibit other serine proteases such as Factor IXa, Factor Xa, Factor XIa, thrombin, trypsin, tryptase, and/or urokinase. Thus, the compounds are useful for treating or preventing those processes which involve the production or action of Factor VIIa and/or other serine proteases.
The compounds of the present invention may be used to treat a variety of diseases including, but not limited to, transplant rejection (e.g., kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts (such as employed in burn treatment), heart valve xenografts, serum sickness, and graft vs. host disease, in the treatment of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (such as Crohn""s disease and ulcerative colitus), pyoderma gangrenum, lupus (systemic lupus erythematosis), myasthenia gravis, psoriasis, dermatitis, dermatomyositis; eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave""s disease, Hashimoto""s thyroiditis, autoimmune thyroiditis, Behcet""s or Sjorgen""s syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, Addison""s disease (autoimmune disease of the adrenal glands), idiopathic adrenal insufficiency, autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), glomerulonephritis, scleroderma, morphea, lichen planus, viteligo (depigmentation of the skin), alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barre syndrome, and alveolitis; in the treatment of T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hayfever, allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); in the treatment of inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, acute respiratory distress syndrome, Sezary""s syndrome and vascular diseases which have an inflammatory and or a proliferatory component such as restenosis, stenosis and artherosclerosis; in the treatment of cancer and tumor disorders, such as solid tumors, lymphomas and leukemia; in the treatment of fungal infections such as mycosis fungoides; in protection from ischemic or reperfusion injury such as ischemic or reperfusion injury that may have been incurred during organ transplantation, myocardial infarction, stroke or other causes; in the treatment of DNA or RNA viral replication diseases, such herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B and hepatitis C) cytomegalovirus, Epstein-Barr, and human immunodeficiency virus (HIV).
Additionally, IMPDH is also known to be present in bacteria and thus may regulate bacterial growth. As such, the IMPDH-inhibitor compounds of the present invention may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
In view of their above-referenced serine protease inhibitory activity, the inventive compounds are useful in treating consequences of atherosclerotic plaque rupture including cardiovascular diseases associated with the activation of the coagulation cascade in thrombotic or thrombophilic states. Such diseases include arterial thrombosis, coronary artery disease, acute coronary syndromes, myocardial infarction, unstable angina, ischemia resulting from vascular occlusion cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack). Additionally, the compounds are useful in treating or preventing formation of atherosclerotic plaques, transplant atherosclerosis, peripheral arterial disease and intermittent claudication. In addition, the compounds can be used to prevent restenosis following arterial injury induced endogenously (by rupture of an atherosclerotic plaque), or exogenously (by invasive cardiological procedures such as vessel wall injury resulting from angioplasty).
In addition, the inventive compounds are useful in preventing venous thrombosis, coagulation syndromes, deep vein thrombosis (DVT), disseminated intravascular coagulopathy, Kasabach-Merritt syndrome, pulmonary embolism, cerebral thrombosis, atrial fibrillation, and cerebral embolism. The compounds are useful in treating peripheral arterial occlusion, thromboembolic complications of surgery (such as hip replacement, endarterectomy, introduction of artificial heart valves, vascular grafts, and mechanical organs), implantation or transplantation of organ, tissue or cells, and thromboembolic complications of medications (such as oral contraceptives, hormone replacement, and heparin, e.g., for treating heparin-induced thrombocytopenia). The inventive compounds are useful in preventing thrombosis associated with artificial heart valves, stents, and ventricular enlargement including dilated cardiac myopathy and heart failure. The compounds are also useful in treating thrombosis due to confinement (i.e. immobilization, hospitalization, bed rest etc.).
These compounds are also useful in preventing thrombosis and complications in patients genetically predisposed to arterial thrombosis or venous thrombosis (including activated protein C resistance, FVleiden, Prothrombin 20210, elevated coagulation factors FVII, FVIII, FIX, FX, FXI, prothrombin, TAFI and fibrinogen), elevated levels of homocystine, and deficient levels of antithrombin, protein C, and protein S. The inventive compounds may be used for treating heparin-intolerant patients, including those with congenital and acquired antithrombin III deficiencies, heparin-induced thrombocytopenia, and those with high levels of polymorphonuclear granulocyte elastase.
The present compounds may also be used to inhibit blood coagulation in connection with the preparation, storage, fractionation, or use of whole blood. For example, the compounds may be used to maintain whole and fractionated blood in the fluid phase such as required for analytical and biological testing, e.g., for ex vivo platelet and other cell function studies, bioanalytical procedures, and quantitation of blood-containing components. The compounds may be used as anticoagulants in extracorpeal blood circuits, such as those necessary in dialysis and surgery (such as coronary artery bypass surgery); for maintaining blood vessel patency in patients undergoing transluminal coronary angioplasty, vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, tumor cell metastasis, and organ, tissue, or cell implantation and transplantation.
In a particular embodiment, compounds of the present invention are useful for treating any one or more of the aforementioned disorders irrespective of their etiology, e.g., for treating arterial thrombosis, coronary artery disease, acute coronary syndromes, myocardial infarction, unstable angina, ischemia, transplant rejection, rheumatoid arthritis, inflammatory bowel disease, and/or viral infections.
The present invention also provides pharmaceutical compositions comprising at least one compound of formula I, or a salt thereof, capable of treating an IMPDH-associated disorder and/or a Factor-VIIa associated disorder, in an amount effective therefor, alone or in combination with at least one additional therapeutic agent, and any pharmaceutically acceptable carrier, adjuvant or vehicle. xe2x80x9cAdditional therapeutic agentxe2x80x9d encompasses, but is not limited to, an agent or agents selected from the group consisting of an immunosuppressant, anti-cancer agent, anti-viral agent, anti-inflammatory agent, anti-fungal agent, antibiotic, anti-vascular hyperproliferation compound, potassium channel opener, calcium channel blocker, sodium hydrogen exchanger inhibitor, anti-arrhythmic agent, thrombin inhibitor, platelet aggregation inhibitor or anti-platelet agent, fibrinogen antagonist, diuretic, anti-hypertensive agent, mineralocorticoid receptor antagonist; phospodiesterase inhibitor; cholesterol/lipid lowering agent; anti-diabetic agent; angiogenesis modulator; anti-coagulant; anti-proliferative agent; anti-tumor agent; and/or anti-infective agent. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
Examples of suitable other anti-inflammatory agents with which the inventive compounds may be used include aspirin, non-steroidal antiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin), TNF-xcex1 inhibitors (such as tenidap and rapamycin or derivatives thereof), or TNF-xcex1 antagonists (e.g., infliximab, OR1384), prednisone, dexamethasone, Enbrel(copyright), cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as Naproxen(copyright), Celebrex(copyright), or Vioxx(copyright)), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, other IMPDH inhibitors, such as mycophenolate (CellCept(copyright)), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, therapies for the treatment of irritable bowel syndrome (e.g., Zelmac(copyright) and Maxi-K(copyright) openers such as those disclosed in U.S. Pat. No. 6,184,231 B1), or other NF-xcexaB inhibitors, such as corticosteroids, calphostin, CSAIDs, 4-substituted imidazo [1,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750; Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; and nuclear translocation inhibitors, such as deoxyspergualin (DSG).
Examples of suitable other antibiotics with which the inventive compounds may be used include cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and CD154 (a.k.a. xe2x80x9cgp39xe2x80x9d), such as antibodies specific for CD40 and/or CD154, fusion proteins constructed from CD40 and/or CD154/gp39 (e.g., CD40Ig and CD8gp39), xcex2-lactams (e.g., penicillins, cephalosporins and carbopenams); xcex2-lactam and lactamase inhibitors (e.g., augamentin); aminoglycosides (e.g., tobramycin and streptomycin); macrolides (e.g., erythromycin and azithromycin); quinolones (e.g., cipro and tequin); peptides and deptopeptides (e.g. vancomycin, synercid and daptomycin) metabolite-based anti-biotics (e.g., sulfonamides and trimethoprim); polyring systems (e.g., tetracyclins and rifampins); protein synthesis inhibitors (e.g., zyvox, chlorophenicol, clindamycin, etc.); and nitro-class antibiotics (e.g., nitrofurans and nitroimidazoles).
Examples of suitable other antifungal agents with which the inventive compounds may be used include fungal cell wall inhibitors (e.g., candidas), azoles (e.g., fluoconazole and vericonazole), and membrane disruptors (e.g., amphotericin B). Examples of suitable other antiviral agents for use with the inventive compounds include nucleoside-based inhibitors, protease-based inhibitors, viral-assembly inhibitors, and other antiviral agents such as abacavir.
Additionally, the inventive compounds may be used in combination with aspirin, clopidogrel, ticlopidine or CS-747, warfarin, and low molecular weight heparins (such as lovenox, enoxaparain, and dalteparin). Other suitable therapeutic agents in combination with which the inventive compounds may be used include anti-arrhythmic agents including Class I agents (such as propafenone); Class II agents (propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K+ channel openers such as IAch inhibitors, and IKur inhibitors (e.g., compounds such as those disclosed in U.S. application Ser. No. 09/729,731, filed Dec. 5, 2000; alpha- or beta-adrenergic blockers (such as propranolol, nadolol and carvedilol), or -xcex2-adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, and/or fenoterol; angiotensin-II receptor antagonists (e.g., irbesartan, losartan or valsartan); anticholinergics such as ipratropium bromide; anti-diabetic agents such as biguanides (e.g. metformin); glucosidase inhibitors (e.g. acarbose); insulins (including insulin secretagogues or insulin sensitizers); meglitinides (e.g. repaglinide); sulfonylureas (e.g., glimepiride, glyburide and glipizide); biguanide/glyburide combinations (e.g., glucovance), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein (aP2) such as those disclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000 and assigned to the present assignee, glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors; anti-bodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and CCD154 (a.k.a. xe2x80x9cgp39xe2x80x9d), such as antibodies specific for CD40 and/or CD154, fusion proteins constructed from CD40 and/or CD154/gp39 (e.g., CD40 Ig and CD8gp39); anti-hypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, lisinopril, zofenopril, ramipril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril), vasopeptidase inhibitors, i.e., dual ACE/NEP inhibitors (e.g., omapatrilat and gemopatrilat), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP) inhibitors; angiogenesis modulators such as endostatin; anti-oxidant agents and/or lipid peroxidation inhibitors such as probucol, BO-653, Vitamin A, Vitamin E, AGI-1067; anti-platelet agents such as GPIIb/GPIIIa blockers, (e.g., abciximab, eptifibatide, tirofiban); P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747); or thromboxane receptor antagonists (e.g., ifetroban); anti-proliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf), cytotoxic drugs such as azathiprine and cyclophosphamide, paclitaxel, and adriamycin; sodium hydrogen exchanger-1 (NHE-1) inhibitors such as cariporide; calcium channel blocking agents such as verapamil, nifedipine, diltiazem, amlodipine and mybefradil; cardiac glycosides such as digitalis and ouabain; diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride; lipid profile modulators including HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin [Nissan/Kowa]), ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin)); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT1 inhibitors; ACAT2 inhibitors; dual ACAT1/2 inhibitors; MTP inhibitors; cholesterol absorption inhibitors; and cholesterol ester transfer protein inhibitors (e.g., CP-529414); PPAR-delta agonists; PPAR-alpha agonists; dual PPAR-alpha/delta agonists; LXR-alpha agonists; LXR-beta agonists; LXR dual alpha/beta agonists; mineralocorticoid receptor antagonists such as spironolactone and eplirinone. thrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, tenecteplase (TNK), lanoteplase (nPA), anisolated streptokinase plasminogen activator complex (ASPAC), Factor VIIa inhibitors, Factor Xa inhibitors, thrombin inhibitors (such as hirudin and argatroban), animal salivary gland plasminogen activators, PAI-1 inhibitors such as XR-330 and T-686, and inhibitors of xcex1-2-antiplasmin such as anti-xcex1-2-antiplasmin antibody, prostacyclin mimetics.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used in the same dosage form with the compound of formula I, in different dosage forms, in those amounts indicated in the Physicians"" Desk Reference (PDR), and/or as otherwise determined by one of ordinary skill in the art.
The compounds of the present invention may act in a synergistic fashion with one or more of the above agents to allow for increased efficacy and/or reduced doses of any of the above agents and therefore minimize potential hemorrhagic side-effects.
The term xe2x80x9cpharmaceutically acceptable carrier, adjuvant or vehiclexe2x80x9d refers to a carrier, adjuvant or vehicle that may be administered to a subject, together with a compound of the present invention, and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, the following: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (xe2x80x9cSEDDSxe2x80x9d) such as d(-tocopherol polyethyleneglycol 1000 succinate), surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as xcex1-, xcex2- and xcex3-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl -xcex2-cyclodextrins, or other solubilized derivatives may also be used to enhance delivery of the compounds of the present invention.
The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 500 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 5 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to IMPDH-associated disorders.
IMPDH Assay
The compounds disclosed herein are capable of targeting and inhibiting IMPDH enzyme. Inhibition can be measured by various methods, including, for example, IMP dehydrogenase HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometric assays (measuring enzymatic production of NADH from NAD). See, e.g., Montero et al., Clinica Chimica Acta 238:169-178 (1995). Additional assays known in the art can be used in ascertaining the degree of activity of a compound (xe2x80x9ctest compoundxe2x80x9d) as an IMPDH inhibitor. The inventors used the following assay to determine the degree of activity of the compounds disclosed herein as IMPDH inhibitors:
Activity of IMPDH I and IMPDH II was measured following an adaptation of the method described in WO 97/40028. The reaction mixture was prepared containing 0.1M Tris pH 8.0, 0.1 M KCl, 3 mM EDTA, 2 mM DTT, 0.4 mM IMP and 40 nM enzyme (IMPDH I or IMPDH II). The reaction was started by the addition of NAD to a final concentration of 0.4 mM. The enzymatic reaction was followed by measuring the increase in absorbance at 340 nM that results from the formation of NADH. For the analysis of potential inhibitors of the enzyme, compounds were dissolved in DMSO to a final concentration of 10 mM and added to the assay mixture such that the final concentration of DMSO was 2.5%. The assay was carried out in a 96-well plate format, with a final reaction volume of 200 xcexcl.
Factor VIIa Assay
Compound was prepared as a 5 mM stock in DMSO, diluted further in DMSO and added directly to the assays. The DMSO concentration for all Factor VIIa studies was less than 1% and compared to DMSO vehicle controls.
Human Factor VIIa was obtained from Enzyme Research Labs (Cat.# HFVIIA 1640). Human recombinant tissue factor (INNOVIN from Dade Behring Cat.# B4212-100; xe2x80x9c20 ml vialxe2x80x9d) was diluted with 8 ml of H2O per vial and diluted further 1:30 into the 302 xcexcl final assay volume. Tissue factor activated FVIIa enzymatic activity was measured in a buffer containing 150 mM NaCl, 5mM CaCl2, 1 mM CHAPS and 1 mg/ml PEG 6000 (pH 7.4) with 1 nM FVIIa and 100 xcexcM D-Ile-Pro-Arg-AFC (Enzyme Systems Products, Km greater than 200 xcexcM) 0.66% DMSO. The assay (302 xcexcl total volume) was incubated at RT for 2 hr prior to reading fluorometric signal (Ex 405/Em 535) using a Victor 2 (Wallac) fluorescent plate reader.
Compounds disclosed herein are capable of inhibiting the enzyme IMPDH and/or Factor VIIa at a measurable level under the above-described assays or other assays known in the field.
The following examples illustrate preferred embodiments of the present invention and do not limit the scope of the present invention which is defined in the claims. Abbreviations employed in the Examples and Schemes previously set forth are defined below.